Hepatitis B virus and HIV co-infection among pregnant women in Rwanda

Hepatitis B virus (HBV) affects people worldwide but the local burden especially in pregnant women and their new born babies is unknown. In Rwanda HIV-infected individuals who are also infected with HBV are su...

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Antimicrobial resistance in Africa: a systematic review

Antimicrobial resistance (AMR) is widely acknowledged as a global problem, yet in many parts of the world its magnitude is still not well understood. This review, using a public health focused approach, aimed ...

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Lessons from a decade of individual-based models for infectious disease transmission: a systematic review (2006-2015)

Individual-based models (IBMs) are useful to simulate events subject to stochasticity and/or heterogeneity, and have become well established to model the potential (re)emergence of pathogens (e.g., pandemic in...

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The predictors of 3- and 30-day mortality in 660 MERS-CoV patients

The mortality rate of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) patients is a major challenge in all healthcare systems worldwide. Because the MERS-CoV risk-standardized mortality rates are curre...

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Antimicrobial resistance in bacterial pathogens among hospitalized children with community acquired lower respiratory tract infections in Dongguan, China (2011–2016)

Bacterial pathogens are a major cause of childhood community acquired lower respiratory tract infections (CA-LRTIs), and few data described the impact of antimicrobial resistance on children with CA-LRTIs. Thi...

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Prevalence and trends in transmitted and acquired antiretroviral drug resistance, Washington, DC, 1999–2014

Drug resistance limits options for antiretroviral therapy (ART) and results in poorer health outcomes among HIV-infected persons. We sought to characterize resistance patterns and to identify predictors of res...

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Supraventricular tachycardia diagnosed by smartphone ECG

Diagnosis of paroxysmal supraventricular tachycardia (PSVT) may be difficult due to its episodic nature, which can be brief and self-limited, limiting the ability for clinicians to diagnose the specific rhythm disorder in a timely manner. We present a case of PSVT, which was unable to be diagnosed through typical evaluation with an event monitor despite several years of symptoms. The patient was ultimately diagnosed using the AliveCor Mobile ECG, a smartphone-based ECG device and application, which he purchased himself and captured a typical atrioventricular node re-entrant tachycardia. The patient was then able to email his cardiologist the tracing, which led to an electrophysiology study and successful slow pathway ablation procedure. Smartphone-based technology has the potential to push diagnostic evaluations outside of the healthcare system and empower patients.

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Dilation of epidural space and posterior soft tissue veins in Hirayama disease

Description

An 18-year-old man presented with distal weakness and amyotrophy of the right hand for a few months. He had no familial or personal medical history. Clinical examination showed atrophy and a marked weakness of right hypothenar and interossei muscles (grade 1/5 on Medical Research Council scale) and a mild weakness of right thumb abduction and wrist extension (4/5). Biceps, brachioradial and triceps tendon reflexes were normal and symmetric. There were no fasciculation, sensory abnormality or pain. Motor nerve conduction studies showed a reduced amplitude of compound muscle action potential of the right ulnar nerve but normal parameters of left ulnar and two median nerves. No focal slowing or conduction block was found. Studies of bilateral median, ulnar and right medial antebrachial cutaneous sensory nerves were normal. Electromyographic examination found active denervation (fibrillation potentials and neurogenic recruitment) in right C8-T1 innervated muscles (abductor pollicis brevis, first dorsal interosseus, extensor...

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Brainstem encephalitis and acute polyneuropathy associated with hepatitis E infection

A 59-year-old man presented with feverish illness. His Glasgow Coma Scale was 15, had reduced visual acuity in the left eye with partial left ptosis and mild left hemiparesis with an extensor left plantar. Over 48 hours, he accrued multiple cranial nerves palsies and progressed to a flaccid paralysis necessitating admission to an intensive care unit.

Cerebrospinal fluid (CSF) study showed 20 lymphocytes and raised protein. Viral and bacterial PCRs were negative. Samples for Lyme, blood-borne viruses, syphilis and autoantibodies were also negative. MRI brain showed T2 abnormalities within the brainstem. Nerve conduction studies revealed an acute motor and sensory axonal neuropathy pattern of Guillian Barre Syndrome (GBS). The patient was treated for both infective and inflammatory causes of brainstem encephalitis and GBS.

Retrospective studies confirmed the presence of hepatitis E virus (HEV) RNA in CSF and serum studies showed positive HEV IgG and IgM prior to intravenous infusion. After 3 months of intensive rehabilitation, the patient was discharged home walking with a frame.

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Eye Movements Reveal Temporal Expectation Deficits in ADHD

A technique that measures tiny movements of the eyes may help scientists better understand and perhaps eventually improve assessment of ADHD, according to new research published in Psychological Science, a journal of the Association for Psychological Science.

Emerging evidence shows that small involuntary eye movements (saccades and microsaccades) are a promising new tool for shedding light on the hidden workings of mental processes like attention and anticipation, cognitive processes that are often impaired in individuals with ADHD. The new study suggests that carefully tracking eye movements offers a new method for empirically monitoring temporal expectation in people with ADHD.

"The eye is restless and eye movements occur constantly, even when observers try to avoid them. Our study shows that this continuous stream of eye movements is temporarily paused before an anticipated visual event," says psychologist and neuroscientist Shlomit Yuval-Greenberg (Assistant Professor at Tel Aviv University), senior author on the study. "This attenuation in eye movements can be used as an estimate for whether and when the occurrence of regular events was indeed predicted."

Yuval-Greenberg and colleagues found that neurotypical individuals (those without a diagnosis of ADHD) tended to have different patterns of eye movements compared with individuals who had an ADHD diagnosis.

"We found that individuals with ADHD tended to not attenuate their eye movements before a predictable event, which suggests that they were not able to predict the event and/or to act upon predictions," Yuval-Greenberg explains.

The team's findings indicate that careful analysis of eye movements may offer an objective measure to complement other tools used for diagnosis and assessing treatment efficacy.

For their study, Yuval-Greenberg and colleagues collected data from a group of 20 individuals who had an ADHD diagnosis and a group of 20 neurotypical controls. Those in the ADHD group were asked to refrain from taking any ADHD-related medication for 24 hours prior to the testing sessions.

On two different days, the participants came into the lab where they were shown a series of colored shapes on a screen while their eye movements were monitored. The participants were instructed to press a key whenever they saw a red square (which appeared around 25% of the time). On one day, participants were shown the shapes at predictable intervals: Every two seconds the next shape would appear. On the other day, the time between shapes varied from 1 to 2.5 seconds. Participants were not told that the timing would be different between the two sessions.

When the stimulus appeared at regular, predictable intervals people in the control group responded more quickly than when it appeared at varied intervals. However, the reaction times of those with ADHD did not improve under predictable conditions.

The researchers also found that those in the control group tended to have fewer eye movements immediately before a predicted event. In contrast, those in the ADHD group did not show the same eye movement slowdown in preparation for an upcoming stimulus.

However, the researchers were surprised to find that an ADHD diagnosis was not the best predictor of an individual's ability to stay focused on the task.

"It is well documented that ADHD is a heterogeneous disorder. It is also documented that only some of the individuals with ADHD experience difficulties in maintaining focused attention throughout a monotonous task," Yuval-Greenberg says. "Yet we were most surprised to reveal that the individual ability to stay focused throughout the task was a better predictor for the attenuation of eye movements than whether or not that individual was diagnosed with ADHD."

This finding is valuable because it demonstrates the importance of assessing the specific neuropsychological functioning of each individual, Yuval-Greenberg explains. And the study highlights the potential use of eye movements as an objective measure of temporal expectation.

Co-authors on the research include Yarden Dankner and Prof. Lilach Shalev of Tel Aviv University and Prof. Marisa Carrasco of New York University.

This study was funded by the Binational United States–Israel National Science Foundation to S. Yuval-Greenberg and M. Carrasco (Grant No. 2013356).

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Assessing Children’s Report of Stool Consistency: Agreement Between the Pediatric Rome III Questionnaire and the Bristol Stool Scale

To assess the agreement between the Questionnaire on Pediatric Gastrointestinal Symptoms–Rome III (QPGS-RIII) and the Bristol Stool Scale (BSS) in evaluating stool consistency and the diagnosis of functional constipation in children.

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Pancreatic Enzyme Replacement Therapy in Children with Severe Acute Malnutrition: A Randomized Controlled Trial

To assess the benefits of pancreatic enzyme replacement therapy (PERT) in children with complicated severe acute malnutrition.

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The Relationship between Coronary Artery Disease Risk Factors and Carotid Intima-Media Thickness in Children

To determine the number of coronary artery disease risk factors and the individual coronary artery disease risk factors that have a negative influence on carotid intima-media thickness in children.

http://ift.tt/2w1Besp

Effectiveness of Pharmacist Interventions on Cardiovascular Risk in Patients With CKD: A Subgroup Analysis of the Randomized Controlled RxEACH Trial

Affecting a substantial proportion of adults, chronic kidney disease (CKD) is considered a major risk factor for cardiovascular (CV) events. It has been reported that patients with CKD are underserved when it comes to CV risk reduction efforts.

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Data Without Numbers

Data: facts about something that can be used in calculating, reasoning, or planning.-Merriam-Webster Dictionary

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Life threatening hemobilia after endoscopic retrograde cholangiopancreatography (ERCP)

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Expression of PD-L1 in Hormone-naïve and Treated Prostate Cancer Patients Receiving Neoadjuvant Abiraterone Acetate plus Prednisone and Leuprolide

Purpose: Programmed cell death ligand-1 (PD-L1)/programmed cell death-1 (PD-1) blockade has been unsuccessful in prostate cancer (PCa), with poor immunogenicity and subsequent low PD-L1 expression in PCa being proposed as an explanation. However, recent studies indicate that a subset of PCa may express significant levels of PD-L1. Further, the androgen antagonist enzalutamide has been shown to up-regulate PD-L1 expression in PCa preclinical models. In this study, we evaluated the effect of neoadjuvant androgen deprivation therapy with abiraterone acetate plus prednisone and leuprolide (Neo-AAPL) on PD-L1 expression in PCa. Experimental Design: Radical prostatectomy (RP) tissues were collected from 44 patients with intermediate-to-high risk PCa who underwent RP after Neo-AAPL treatment. Untreated PCa tissues were collected from 130 patients, including 44 matched controls for the Neo-AAPL cases. Tumor PD-L1 expression was detected by immunohistochemistry using validated anti-PD-L1 antibodies. Tumor-infiltrating CD8+ cells were analyzed in trial cases and matched controls. Expression of DNA mismatch repair genes was examined in PD-L1-positive tumors. Results: Neo-AAPL-treated tumors showed a trend toward decreased PD-L1 positivity compared to matched controls (7% vs 21% having ≥1% positive tumor cells; p = 0.062). Treated tumors also harbored significantly less tumor-infiltrating CD8+ cells (p = 0.029). In 130 untreated PCas, African American, elevated serum PSA, and small prostate independently predicted tumor PD-L1 positivity. Loss of MSH2 expression was observed in one of twenty-one PD-L1-positive tumors. Conclusions: A subset of PCa expresses PD-L1, which is not increased by Neo-AAPL treatment, indicating that combining Neo-AAPL treatment with PD-L1/PD-1 blockade may not be synergistic.

http://ift.tt/2wTdGVZ

Albumin Prevents Infections in Patients with Chronic Liver Failure in a Single-arm Feasibility Trial

Infections are life threatening to patients with acute decompensation and acute-on-chronic liver failure (AD/ACLF). Patients with AD/ACLF have prostaglandin E2-mediated immune suppression, which can be reversed by administration of albumin; infusion of 20% human albumin solution (HAS) might improve outcomes of infections. We performed a feasibility study to determine optimal trial design, assess safety, and validate laboratory assessments of immune function to inform design of a phase 3 trial.

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Suboptimal Interobserver Agreement Among Cytopathologists for Endoscopic Ultrasound Fine Needle Aspirates of Solid Pancreatic Lesions

Despite the widespread use of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) and the standardization of pancreaticobiliary cytopathologic nomenclature, data on interobserver agreement (IOA) amongst cytopathologists evaluating pancreatic tissue specimens are limited. We aimed to assess IOA among cytopathologists evaluating EUS-FNA specimens of solid pancreatic lesions for overall cytologic diagnosis and quantitative and qualitative parameters using a novel standardized scoring tool and to evaluate predictors of agreement.

http://ift.tt/2jkFkWx

Postprandial High Resolution Impedance Manometry Identifies Mechanisms of Non-Response to Proton Pump Inhibitors

Recognition of rumination and supragastric belching is often delayed as symptoms may be mistakenly attributed to gastroesophageal reflux disease (GERD). However, distinct from GERD, rumination and supragastric belching are more responsive to behavioral interventions than to acid-suppressive and anti-reflux therapies. Postprandial high-resolution impedance manometry (PP-HRIM) is an efficient method to identify rumination and belches. We investigated the distribution of postprandial profiles determined by PP-HRIM, and identified patient features associated with postprandial profiles among patients with non-response to proton pump inhibitors (PPIs).

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Pearly esophageal papules: An innocent bystander in the evaluation of dysphagia

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Anniversary Tribute from the Editors of Clinical Gastroenterology and Hepatology

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Preoperative Panel Testing for Hereditary Cancer Syndromes Does Not Significantly Impact Time to Surgery for Newly Diagnosed Breast Cancer Patients Compared with BRCA1/2 Testing

Abstract

Background

This study seeks to determine whether there is a delay in time to surgery in breast cancer patients with panel tests compared with traditional BRCA testing.

Methods

This study was a retrospective review of women diagnosed with breast cancer who underwent genetic evaluation from our institution's Genetic Counselor Database from January 2013 to August 2015. Patients were excluded if they were male, clinical information was unavailable, the patient underwent neoadjuvant chemotherapy, had a diagnosis of recurrent breast cancer during time of study, or had postoperative genetics evaluation.

Results

Included in the study were 138 patients. The time from diagnosis to surgery for BRCA1/2 tested patients was 43.5 days compared with 51.0 days in the panel group (p = 0.186). Turnaround time for genetic testing decreased during the period studied and was approximately 6 days longer for panel testing than BRCA testing. It took 12.2 days for BRCA results and 18.9 days for the panel results (p < 0.01). Turnaround time for BRCA1/2 testing in 2014 and 2015 was 12.4 and 10.5 days respectively, whereas panel testing was 20.5 and 18.2 days (p ≤ 0.001). Of the variables included in multivariable linear regression, only mastectomy significantly contributed to time to surgery (p < 0.001).

Discussion

Panel genetic testing did not delay time to surgery compared with BRCA testing alone. The use of panel testing has increased over time, and lab turnaround time has decreased. Mastectomy was the only clinical variable contributing to longer time to surgery.

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Factors Influencing Management and Outcome in Patients with Occult Breast Cancer with Axillary Lymph Node Involvement: Analysis of the National Cancer Database

Abstract

Background

Occult breast cancer (OBC) is rare and optimal local–regional (LR) management has not been defined. Using a patient registry database, we examine factors associated with treatment and outcomes in OBC.

Methods

Female patients with cT0 N1/2 M0 BC were selected from the National Cancer Database (2004–2013) and categorized into four treatment groups: MAST = mastectomy with axillary lymph node dissection (ALND) ± radiation (RT); RT + ALND = RT with ALND, no breast surgery; ALND = ALND alone; OBS = no breast surgery, RT, or ALND. Patient characteristics and overall survival (OS) were compared between groups, and multivariable analysis was used to identify factors associated with treatment and OS.

Results

Among 2.03 million BC cases, 1853 females (0.09%) with cT0 N1/2 M0 disease were identified and 1231 patients were categorized into a treatment group: MAST = 592, RT + ALND = 342, ALND = 106, OBS = 191. On logistic regression, care at an academic center was associated with a higher likelihood of RT + ALND compared with MAST (odds ratio 2.03, 95% confidence interval [CI] 1.50–2.74, p < 0.001). Patients treated with RT + ALND had significantly better OS on univariate survival analysis compared with patients treated with MAST (hazard ratio [HR] 0.475, 95% CI 0.306–0.736, p = 0.001). RT + ALND was independently associated with OS on multivariable survival analysis (HR 0.509, 95% CI 0.321–0.808, p = 0.004), after adjusting for covariates.

Conclusions

Patients with OBC were more likely to undergo RT + ALND if they received care at an academic center. Patients treated with RT + ALND had significantly better OS compared with patients treated with MAST, after adjusting for covariates. This supports the use of RT + ALND as LR treatment for patients with OBC.

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Presidential Address: The Road Ahead—Challenges and Opportunities

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Expanded Gene Panel Use for Women With Breast Cancer: Identification and Intervention Beyond Breast Cancer Risk

Abstract

Background

Clinicians ordering multi-gene next-generation sequencing panels for hereditary breast cancer risk have a variety of test panel options. Many panels include lesser known breast cancer genes or genes associated with other cancers. The authors hypothesized that using broader gene panels increases the identification of clinically significant findings, some relevant and others incidental to the testing indication. They examined clinician ordering patterns and compared the yield of pathogenic or likely pathogenic (P/LP) variants in non-BRCA genes of female breast cancer patients.

Methods

This study analyzed de-identified personal and family histories in 1085 breast cancer cases with P/LP multi-gene panel findings in non-BRCA cancer genes and sorted them into three groups by the panel used for testing: group A (breast cancer genes only), group B (commonly assessed cancers: breast, gynecologic, and gastrointestinal), and group C (a more expanded set of tumors). The frequency of P/LP variants in genes with established management guidelines was compared and evaluated for consistency with personal and family histories.

Results

This study identified 1131 P/LP variants and compared variants in clinically actionable genes for breast and non-breast cancers. Overall, 91.5% of these variants were in genes with management guidelines. Nearly 12% were unrelated to personal or family history.

Conclusion

Broader panels were used for 85.6% of our cohort (groups B and C). Although pathogenic variants in non-BRCA genes are reportedly rare, the study found that most were in clinically actionable genes. Expanded panel testing improved the identification of hereditary cancer risk. Small, breast-limited panels may miss clinically relevant findings in genes associated with other heritable cancers.

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Breast Cancer-Related Lymphedema Risk is Related to Multidisciplinary Treatment and Not Surgery Alone: Results from a Large Cohort Study

Abstract

Background

Breast cancer-related lymphedema (BCRL) is a significant complication for women undergoing treatment. We assessed BCRL incidence and risk factors in a large population-based cohort.

Methods

We utilized the Olmsted County Rochester Epidemiology Project Breast Cancer Cohort from 1990–2010 and ascertained BCRL and risk factors. The cumulative incidence estimator was used to estimate the rate of BCRL; competing risks regression was used for multivariable analysis.

Results

A total of 1794 patients with stage 0–3 breast cancer with a median of 10 years follow-up were included. The cumulative incidence of BCRL diagnosis within 5 years was 9.1% [95% confidence interval (CI) 7.8–10.5%]. No BCRL events occurred among patients without axillary surgery. In the axillary surgery subset (n = 1512), the 5-year incidence of BCRL was 5.3% in sentinel lymph node (SLN) surgery and 15.9% in axillary dissection (ALND) patients (p < 0.001). In patients treated with surgery only, BCRL rates were not different between ALND versus SLN (3.5 and 4.1% at 5 years, p = 0.36). Addition of breast or chest wall radiation more than doubled the BCRL rate in ALND patients (3.5 vs. 9.5% at 5 years, p = 0.01). The groups with highest risk (>25% at 5 years) all involved ALND with nodal RT and/or anthracycline/cytoxan + taxane chemotherapy. In multivariable analysis of patients with any axillary surgery factors significantly associated with BCRL were ALND, chemotherapy, radiation, and obesity.

Conclusions

BCRL is a sequelae of multimodal breast cancer treatment and risk is multifactorial. BCRL rates are higher in patients receiving chemotherapy, radiation, ALND, more advanced disease stage, and higher body mass index.

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Clinical Decision-Making in Patients with Variant of Uncertain Significance in BRCA1 or BRCA2 Genes

Abstract

Background

How diagnosis with a variant of uncertain significance (VUS) in a BRCA gene impacts clinical decision-making is not well known.

Methods

We queried for all patients attending Mayo Clinic Rochester from 2004 to 2016 who tested positive for BRCA1 or BRCA2 VUS and reviewed patient management choices. Groups were compared by using Wilcoxon rank-sum and Chi-square tests.

Results

We identified 97 patients (95 females, 2 males) with BRCA VUS. For patients without cancer history (n = 20), 80% had a mother or sister with breast cancer, and median Tyrer-Cuzick (IBIS) lifetime breast cancer risk score was 27% (range 16–62%). Management included bilateral prophylactic mastectomy (BPM) in 39%, where choice for BPM was significantly associated with IBIS score (median 32 vs. 24%, p = 0.02) and first-degree family history of breast cancer (100 vs. 64%, p = 0.03) but not Gail score or total number of family members with cancer. For patients with breast cancer who had known VUS status prior to surgery (n = 9), the rate of contralateral prophylactic mastectomy (CPM) was 22% compared with 25% without known VUS and 83% with known BRCA pathogenic mutation. In 21 of 97 (22%) patients, the BRCA VUS has been reclassified (95% benign, 5% deleterious).

Conclusions

BRCA VUS carriers with cancer elected surgical choices similar to average-risk breast cancer patients. However, VUS carriers without cancer had high rates of BPM, associated with first-degree family history and IBIS score. Over time, a significant proportion of BRCA VUS were reclassified, illustrating the importance of appropriate counseling regarding VUS.

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Contralateral Prophylactic Mastectomy with Immediate Breast Reconstruction Increases Healthcare Utilization and Cost

Abstract

Background

The rates of contralateral prophylactic mastectomy (CPM) in women with unilateral breast cancer continue to rise, especially in women undergoing immediate breast reconstruction (IBR).

Methods

We utilized administrative claims data from a large US commercial insurance database (OptumLabs) to identify women age 18–64 years who underwent IBR between January 2004 and December 2013. We compared 2-year unadjusted utilization rates and total costs of care between unilateral mastectomy (UM) and bilateral mastectomy (BM) for implant-based and autologous reconstruction. Comparisons were tested using t-test and differences in cost were estimated using the Wilcoxon rank-sum test.

Results

Overall, 11,235 women undergoing mastectomy with IBR were identified; 7319 with implant reconstruction [1923 UM (26%) and 5396 BM (74%)] and 3916 with autologous reconstruction [1687 UM (43%) and 2229 BM (57%)]. The overall rate of office visits (2386 vs. 2391 per 100 women, p = 0.42) and hospital readmission rate (29.1 per 100 women vs. 27.4, p = 0.06) were similar between BM + IBR and UM + IBR. Women undergoing BM + IBR had a higher emergency room (ER) visit rate (34.1 per 100 women vs. 29.8, p < 0.0001). The total 2-year cost of care was higher for BM + IBR than UM + IBR for implant reconstruction ($106,711 vs. $97,218, p < 0.0001) and for autologous reconstruction ($114,725 vs. $87,874, p < 0.0001).

Conclusions

BM + IBR (autologous or implant) was associated with increased ER visits and higher total cost of care over 2 years compared with UM + IBR. Patients considering CPM should be counseled on the additional risks and costs associated with BM + IBR.

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Evaluating the Risk of Upstaging HER2-Positive DCIS to Invasive Breast Cancer

Abstract

Background

Overexpression of human epidermal growth factor 2 (HER2) in invasive breast cancer (IBC) is an independent poor prognostic factor. However, the significance of HER2 overexpression in ductal carcinoma in situ (DCIS) is not well defined. The current study assessed the correlation of HER2⁺ DCIS with the rate of upstaging to IBC on the final pathology.

Methods

The study retrospectively analyzed patients with the diagnosis of DCIS on core needle biopsy (CNB) at the authors' institution from 2009 to 2016. Data were analyzed using two-sample t tests. Multivariate analysis was performed using logistic regression.

Results

The study found that HER2⁺ DCIS had significantly higher rates of upstaging to IBC than HER2⁻ DCIS (odds ratio [OR] 1.89; p = 0.012). In addition, triple-positive disease was more than two times more likely to be upstaged (OR 2.5; p = 0.01), whereas patients with estrogen (ER)-positive, progesterone (PR)-positive, and HER2⁻ diseases were half as likely to be upstaged (OR 0.5; p = 0.04). Upstaging did not differ for patients with triple-negative disease (OR 0.89; p = 0.8). Additionally, patients with HER2⁺ DCIS were significantly younger regardless of ER/PR status (p = 0.03). The overexpression of HER2 in patients with an initial diagnosis of DCIS on CNB were twice as likely to have IBC on the final pathology as those who did not.

Conclusion

The results suggest that overexpression of HER2 may serve as a biomarker for risk stratification of patients with DCIS and may help to guide treatment strategies in the future. For institutions in which HER2 testing may be performed on DCIS, patients should be counseled appropriately about the risk of upgrade to IBC.

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A 10-Year Experience with Mastectomy and Tissue Expander Placement to Facilitate Subsequent Radiation and Reconstruction

Abstract

Background

An integrated approach to skin sparing mastectomy with tissue expander placement followed by radiotherapy and delayed reconstruction was initiated in our institution in 2002. The purpose of this study was to assess the surgical outcomes of this strategy.

Methods

Between September 2002 and August 2013, a total of 384 reconstructions had a tissue expander placed at the time of mastectomy and subsequently underwent radiotherapy. Rates and causes of tissue expander explantation before, during, and after radiotherapy, as well as tumor specific outcomes and reconstruction approaches, were collected.

Results

Median follow-up after diagnosis was 5.6 (range 1.3–13.4) years. In the study cohort, 364 patients (94.8%) had stage II–III breast cancer, and 7 patients (1.8%) had locally recurrent disease. The 5-year rates of actuarial locoregional control, disease-free survival, and overall survival were 99.2, 86.1, and 92.4%, respectively. The intended delayed-immediate reconstruction was subsequently completed in 325 of 384 mastectomies (84.6% of the study cohort). Of the remaining 59 tissue expanders, 1 was explanted before radiotherapy, 1 during radiotherapy, and 7 patients (1.8%) were lost to follow-up. Fifty patients (13.0%) required tissue expander explantation after radiation and before their planned final reconstruction, primarily due to cellulitis. Nonetheless, the cumulative rate of completed reconstructions was 89.6%. The median time from placement of the tissue expander until reconstruction was 12 (interquartile range 9–15) months.

Conclusions

Tissue expander placement at skin-sparing mastectomy in patients who require radiotherapy appears to be a viable strategy for combining reconstruction and radiotherapy.

http://ift.tt/2f0OOEL

Predicting Nodal Positivity in Women 70 Years of Age and Older with Hormone Receptor-Positive Breast Cancer to Aid Incorporation of a Society of Surgical Oncology Choosing Wisely Guideline into Clinical Practice

Abstract

Purpose

One of the Society of Surgical Oncology Choosing Wisely guidelines recommends avoiding routine sentinel lymph node (SLN) surgery in clinically node-negative women ≥70 years of age with hormone receptor-positive (HR+) breast cancer. We sought to assess the impact of tumor stage and grade on nodal positivity, and to develop a model to identify patients at low-risk of nodal positivity to aid adoption of the guideline.

Methods

We identified women ≥70 years of age with HR+ cN0 invasive breast cancer in the National Cancer Database (NCDB; 2010–2013) and examined the impact of tumor stage and grade on nodal positivity to identify low-risk combinations. A multivariable logistic regression model was developed to incorporate additional factors. The area under the curve (AUC) and relative risks (RR) were used to assess performance.

Results

Among 71,834 cases, the pathologic nodal positivity (pN+) rate was 15.3%. We identified low-risk criteria as grade 1, cT1mi-T1c (≤2.0 cm), or grade 2, cT1mi-T1b (≤1.0 cm), with pN+ rates of 7.8% compared with 22.3% in patients not meeting these criteria (RR 2.86, p < 0.001). On multivariable analysis, factors associated with pN+ status included clinical T stage, grade, and histology (each p < 0.001). The resulting model had AUC 0.70 and identified women with low predicted probability (<10%) of positive nodes, of whom 6.3% were pN+, versus 21.2% in those with predicted probability ≥10% (RR 3.34, p < 0.001).

Conclusion

The simple clinical rule (grade 1, cT1mi-T1c, or grade 2, cT1mi-T1b), as well as the predictive model, both identify women at low risk of nodal positivity where SLN surgery can be omitted.

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Influence of Distance to Hospital and Insurance Status on the Rates of Contralateral Prophylactic Mastectomy, a National Cancer Data Base study

Abstract

Introduction

We evaluated the impact of travel distance and insurance status on contralateral prophylactic mastectomy (CPM) rates in breast cancer.

Methods

We queried the National Cancer Data Base (NCDB) for women >18 years of age with a nonmetastatic primary breast cancer of ductal, lobular, or mixed histology. Patient- and facility-specific CPM rates were calculated based on insurance, race, and distance to treatment center. Standard univariable and multivariable regression analysis was performed.

Results

Overall, the CPM rate was 6.5% for the 864,105 patients identified. Most patients traveled <20 miles to a treatment center (79.5%) and had private insurance or Medicare (58.3 and 33.4%, respectively). In general, younger, White, non-Hispanic, and privately insured patients residing further from a treatment center was associated with increased rates of CPM. However, distance to the treatment center and insurance type had a greater absolute impact on rates of CPM for Black and Hispanic patients. Absolute CPM rate increases for patients >100 miles from a treatment center compared with those <20 miles from a treatment center were observed to be greater for Black and Hispanic patients (3.5 and 3.9%, respectively) compared with White and non-Hispanic patients (2.5 and 2.6%). Additionally, further patient travel distance was associated with higher treatment center-specific CPM rates.

Conclusion

Increased travel distance is independently associated with increased rates of CPM for all patients and increased facility-specific rates of CPM. Black and Hispanic patients were found to be more vulnerable to the impact of travel distance and insurance status on rates of CPM.

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Challenging Atypical Breast Lesions Including Flat Epithelial Atypia, Radial Scar, and Intraductal Papilloma

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Artificial Intelligence in a New Context: “Internal” and “External” Factors

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VHL deficiency drives enhancer activation of oncogenes in clear cell renal cell carcinoma [Research Articles]

Protein-coding mutations in clear cell renal cell carcinoma (ccRCC) have been extensively characterized, frequently involving inactivation of the von Hippel Lindau (VHL) tumor suppressor. Roles for non-coding cis-regulatory aberrations in ccRCC tumorigenesis, however, remain unclear. Analyzing 10 primary tumor/normal pairs and 9 cell lines across 79 chromatin profiles, we observed pervasive enhancer malfunction in ccRCC, with cognate enhancer-target genes associated with tissue-specific aspects of malignancy. Super-enhancer profiling identified ZNF395 as a ccRCC-specific and VHL-regulated master regulator, whose depletion causes near-complete tumor elimination in vitro and in vivo. VHL loss predominantly drives enhancer/super-enhancer deregulation more so than promoters, with acquisition of active enhancer marks (H3K27ac, H3K4me1) near ccRCC hallmark genes. Mechanistically, VHL loss stabilizes HIF2α-HIF1β heterodimer binding at enhancers, subsequently recruiting histone acetyltransferase P300 without overtly affecting pre-existing promoter-enhancer interactions. Subtype-specific driver mutations such as VHL may thus propagate unique pathogenic dependencies in ccRCC by modulating epigenomic landscapes and cancer gene expression.

http://ift.tt/2w2CWcF

Galectin-3, a druggable vulnerability for KRAS-addicted cancers [Research Articles]

Identifying the molecular basis for cancer cell dependence on oncogenes such as KRAS can provide new opportunities to target these addictions. Here, we identify a novel role for the carbohydrate-binding protein Galectin-3 as a lynchpin for KRAS dependence. By directly binding to the cell surface receptor integrin αvβ3, Galectin-3 gives rise to KRAS addiction by enabling multiple functions of KRAS in anchorage-independent cells, including formation of macropinosomes that facilitate nutrient uptake and ability to maintain redox balance. Disrupting αvβ3/Galectin-3 binding with a clinically active drug prevents their association with mutant KRAS, thereby suppressing macropinocytosis while increasing reactive oxygen species to eradicate αvβ3-expressing KRAS mutant lung and pancreatic cancer patient-derived xenografts and spontaneous tumors in mice. Our work reveals Galectin-3 as a druggable target for KRAS-addicted lung and pancreas cancer, and indicates integrin αvβ3 as a biomarker to identify susceptible tumors.

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Sexual Orientation and Gender Identity Issues in Schools: Advocacy, Research, and Global Perspectives

http://ift.tt/2w3Ewep

The Impact of Different Forms of #fitspiration Imagery on Body Image, Mood, and Self-Objectification among Young Women

Abstract

The present study experimentally examined the impact of different forms of inspirational fitness images ("fitspiration") on women's body image. Australian female participants (n = 152, 17–30 years-old; M _age = 21.55, SD = 3.94) were randomly assigned to view fitspiration media which depicted the body in a functional (performing exercise) or non-functional (posed) way, with or without accompanying appearance-focused text. There were no main effects of image type or text presence for body satisfaction, mood, or state self-objectification. However, state body satisfaction decreased and negative mood increased over time following exposure to the fitspiration images. Trait self-objectification moderated the impact of image type and text on state body satisfaction, such that viewing functional images presented with appearance-focused text resulted in poorer body satisfaction for women with higher trait self-objectification, but not for those with lower self-objectification. The findings demonstrate that irrespective of focus or presence of text, exposure to fitspiration images decreases body satisfaction and increases negative mood, highlighting the potential negative consequences of engaging with fitspiration media.

http://ift.tt/2y18jBM

Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis

Fragility fractures are common and increase morbidity and mortality. Romosozumab (Amgen and UCB Pharma) is a new bone-forming monoclonal antibody that binds to and inhibits sclerostin, with a dual effect of increasing bone formation and decreasing bone resorption. In a randomized, controlled trial,…

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Comparison of Single Genome and Allele Frequency Data Reveals Discordant Demographic Histories

Inference of demographic history from genetic data is a primary goal of population genetics of model and non-model organisms. Whole genome-based approaches such as the Pairwise/Multiple Sequentially Markovian Coalescent (PSMC/MSMC) methods use genomic data from one to four individuals to infer the demographic history of an entire population, while site frequency spectrum (SFS)-based methods use the distribution of allele frequencies in a sample to reconstruct the same historical events. Although both methods are extensively used in empirical studies and perform well on data simulated under simple models, there have been only limited comparisons of them in more complex and realistic settings. Here we use published demographic models based on data from three human populations (Yoruba (YRI), descendants of northwest-Europeans (CEU), and Han Chinese (CHB)) as an empirical test case to study the behavior of both inference procedures. We find that several of the demographic histories inferred by the whole genome-based methods do not predict the genome-wide distribution of heterozygosity nor do they predict the empirical SFS. However, using simulated data, we also find that the whole genome methods can reconstruct the complex demographic models inferred by SFS-based methods, suggesting that the discordant patterns of genetic variation are not attributable to a lack of statistical power, but may reflect unmodeled complexities in the underlying demography. More generally, our findings indicate that demographic inference from a small number of genomes, routine in genomic studies of non-model organisms, should be interpreted cautiously, as these models cannot recapitulate other summaries of the data.

http://ift.tt/2xsJOAr

Highly Efficient, Rapid and Co-CRISPR Independent Genome Editing in Caenorhabditis elegans

We describe a rapid and highly efficient method to generate point mutations in C. elegans using direct injection of CRISPR-Cas9 ribonucleoproteins. This versatile method does not require sensitized genetic backgrounds or co-CRISPR selection-based methods, and represents a single strategy that can used for creating genomic point mutations, regardless of location. As proof-of-principle, we show that knock-in mutants more faithfully report variant-associated phenotypes compared to transgenic overexpression. Data for nine knock-in mutants across five genes are presented that demonstrate high editing efficiencies (60%), a reduced screening workload (24 F1 progeny), and a rapid timescale (4-5 days). This optimized method simplifies genome engineering and is readily adaptable to other model systems.

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Immune monitoring for precision medicine in allergy and asthma

Scott Dexter Boyd | Ramona Amy Hoh | Kari Christine Nadeau | Stephen Joseph Galli

http://ift.tt/2xt1qfL

Immune mechanisms of food allergy and its prevention by early intervention

Victor Turcanu | Helen A Brough | George Du Toit | Ru-Xin Foong | Tom Marrs | Alexandra F Santos | Gideon Lack

http://ift.tt/2h0vZyv

Lesion Pattern, Mechanisms, and Long-Term Prognosis in Patients with Monoparetic Stroke: A Comparison with Nonmonoparetic Stroke

Background. Monoparetic stroke is rare but could be misdiagnosed as peripheral neuropathy. We investigated the prevalence, lesion pattern, stroke mechanism, and long-term prognosis in patients with monoparetic stroke. Methods. 586 acute ischemic stroke patients (including 31 with monoparesis) were studied. Monoparetic stroke was defined as a motor deficit in either an arm or a leg but without facial weakness or speech disturbance. Median follow-up period was 32.0 months. Kaplan-Meier survival curves, log-rank tests, logistic regressions, and Cox proportional hazards models were used for clinical outcome analyses. Results. The mean age (313 men and 273 women) was 67.6 years. Among monoparetic patients, most had cortical (80.6%) and multiple (64.5%) lesions. The main stroke mechanisms were cardioembolism (38.7%) and large artery atherosclerosis (29.0%). Precentral gyrus with additional regions was most frequently involved in monoparesis (45.2%). Upper motor neuron signs were found in only 11 patients (35.5%). Compared with the nonmonoparetic group, these patients had better functional outcomes (6-month modified Rankin scale ≤2) and long-term survival but had comparable risks for further vascular events, including stroke recurrences. Conclusions. Although monoparetic stroke may have a better functional outcome, the risk of the further vascular event seems similar to nonmonoparetic stroke.

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Markers of Alzheimer’s Disease in Primary Visual Cortex in Normal Aging in Mice

Aging is the principal risk factor for the development of Alzheimer's disease (AD). The hallmarks of AD are accumulation of the amyloid-β peptide 1–42 (Aβ42) and abnormal hyperphosphorylation of Tau (p-Tau) protein in different areas of the brain and, more recently reported, in the visual cortex. Recently, Aβ42 peptide overproduction has been involved in visual loss. Similar to AD, in normal aging, there is a significant amyloid deposition related to the overactivation of the aforementioned mechanisms. However, the mechanisms associated with visual loss secondary to age-induced visual cortex affectation are not completely understood. Young and aged mice were used as model to analyze the presence of Aβ42, p-Tau, glial-acidic fibrillary protein (GFAP), and presenilin-2, one of the main enzymes involved in Aβ42 production. Our results show a significant increase of Aβ42 deposition in aged mice in the following cells and/or tissues: endothelial cells and blood vessels and neurons of the visual cortex; they also show an increase of the expression of GFAP and presenilin-2 in this region. These results provide a comprehensive framework for the role of Aβ42 in visual loss due to inflammation present with aging and offer some clues for fruitful avenues for the study of healthy aging.

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Genetic Polymorphisms of Manganese-Dependent Superoxide Dismutase in Chagas Disease.

Background: Infection with Trypanosoma cruzi triggers inflammatory mechanisms and induces the activity of manganese-dependent superoxide dismutase. Genetic single-nucleotide polymorphisms of this enzyme generate proteins with reduced enzymatic activity. The aims of this study were to determine the frequency of the polymorphisms Ala-9Val and Ile58Thr of the manganese-dependent superoxide dismutase gene in DNA from chagasic and nonchagasic patients and to establish a relationship between these polymorphisms with chronic chagasic cardiomyopathy. Methods: Two hundred fifty-eight unrelated patients underwent a general clinical examination and an electrocardiogram, a chest radiograph, and a 12-lead color Doppler echocardiogram were taken. Besides, we evaluate liver and renal function, lipid profile, and diagnosis of Chagas disease and genetic polymorphisms by polymerase chain reaction-restriction fragment length polymorphism. The patients were classified as nonchagasic group with negative serology for Chagas disease and the chagasic group with positive serology. This group was subdivided into asymptomatic when patients did not present abnormal cardiac symptoms and symptomatic if the chest radiograph, electrocardiogram, and/or color Doppler echocardiogram showed some alteration. Results: The female chagasic population shows a high frequency of the ile58ile genotype (P = 0.010; odds ratio, 3.3; 95% confidence interval, 1.35-8.38). Lower frequency of the ala-9ala genotype was detected in symptomatic Chagas patients (P = 0.001; odds ratio, 3.147; 95% confidence interval, 1.39-7.482). The analysis revealed an interaction between the ala/ala + val/val genotype (P = 0.0108) with the plasma concentration of low-density lipoprotein cholesterol in the symptomatic Chagas group. Conclusions: Our results show that the presence of the val allele is associated with chronic chagasic cardiomyopathy. The prognostic value of these results should be more deeply investigated. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Disseminated Mycobacterium Haemophilum Infection Masquerading as Erythema Nodosum and Avascular Necrosis in an Immunocompromised Host.

Mycobacterium haemophilum is likely an underrecognized cause of infection among patients with deficits in their cell-mediated immunity. Despite its name, which translates to "blood loving," it remains unclear whether hyperferritinemic patients are also at higher risk of this infection. We present a 24-year-old woman with disseminated M. haemophilum infection who has hyperferritinemia and T-cell acute lymphoblastic leukemia in remission and was initially misdiagnosed as having erythema nodosum and avascular necrosis. This report highlights the clinical and histological similarities of M. haemophilum and erythema nodosum, discusses some diagnostic peculiarities, and also reviews similar cases within the literature. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Spinal Epidural Abscess Caused by Gardnerella vaginalis and Prevotella amnii.

We report a case of spinal epidural abscess in a 58-year-old woman who had recently been diagnosed with gonococcal infection, but did not receive guideline-recommended therapy. She presented with back pain as well as signs and symptoms of pelvic inflammatory disease (PID). Magnetic resonance imaging of the spine demonstrated epidural abscess extending from T10 to L4/L5. She underwent T10/L1 and L3/L4 laminectomies for evacuation of the abscess and Gardnerella vaginalis and Prevotella amnii were isolated from the abscess fluid cultures. Our case demonstrates spinal epidural abscess as a rare, but morbid complication of PID and highlights the pathogenic potential of the anaerobic flora associated with PID. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Mycobacterium Tuberculosis Diversity by Exact Tandem Repeats-Variable Number Tandem Repeat Method in Azerbaijan, Iran.

Background: Tuberculosis (TB) is the leading cause of adult deaths among infectious agents. One of the genetic fingerprinting techniques to study the epidemiology of TB is variable number tandem repeat (VNTR). The purpose of this study was to determine the diversity of Mycobacterium tuberculosis isolated from patients in Azerbaijan, Iran by exact tandem repeats (ETR)-VNTR method. Methods: We used the ETR-VNTR method to analyze the genotypes of M. tuberculosis isolates. Forty-seven isolates were collected from pulmonary and extra pulmonary Tuberculosis patients associated with epidemiological data such as human immunodeficiency virus, anti-TB drugs use, cigarette smoking, diabetes mellitus, lung cancer, contact with TB patients, Bacillus Calmette-Guerin vaccine use, cough, housekeeping, fever, and other risk factors from April 2013 to February 2015 in Tabriz Research Center of Tuberculosis and Lung Disease. Three loci ETR-A, ETR-B, and ETR-C of VNTR patterns were studied. The patients' data were checked to determine the relationships between the epidemiological data and M. tuberculosis diversities. Results: Among the 47 isolates, 45 separate ETR-VNTR patterns consist of 9 clusters, 24 nonclusters (unique patterns) were found. No locus was observed in 2 samples. Diabetes and close household contacts were identified as important risk factors for TB in our subjects with unique patterns. Conclusions: Thirty-three distinct patterns were distinguished. In the case of respiratory symptoms in patients with diabetes and close household contact patients, TB can be considered as the important differential diagnosis with unique patterns. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Streptococcus pyogenes Bacteremia in Adults in the 21st Century: Review of 68 Episodes Over 10-Year Period in a Large Community Teaching Hospital.

Background: Streptococcus pyogenes causes pharyngitis, tonsillitis, cellulitis, and less frequently other clinical syndromes. It is infrequently included in the differential diagnosis of other infectious illnesses. Methods: We reviewed the medical records of all adult patients (16 years of age and older) with S. pyogenes bacteremia admitted to our institution during the 10 years from January 1, 2007, to December 31, 2016. We report the epidemiology, source of infection, comorbid conditions, treatment, and mortality for these patients. Results: There were 68 cases of S. pyogenes bacteremia during the study period. There were 27 episodes in men (39.7%) and 41 episodes in women (60.3%). The patients' ages ranged from 17 to 91 years with a mean of 58.1 years and a median of 59.5 years. Skin and soft tissue infections with or without necrotizing fasciitis were the most common presentation followed by primary bacteremia, pneumonia, septic bursitis/arthritis, obstetric/gynecologic, and head/neck infections. All strains of S. pyogenes tested during the study period maintained sensitivity to penicillin G. Diabetes mellitus was the most common comorbid condition. Seven of 68 patients died for a mortality rate of 10.3%. Conclusions: Bacteremic S. pyogenes infections continue to be a significant clinical problem years into the 21st century. Resident physicians, hospitalists, intensivists, and surgeons should be keenly aware of this information and understand the potential consequences of unrecognized, rapidly progressive group A streptococcal infection. Emergent surgical intervention remains essential to the survival of many of these patients. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Prion Disease: A Review of Novel Transmission Methods and Efforts at Discovering Preventive and Therapeutic Modalities.

Since the discovery of Prion Proteins (PrPs) in 1982, a new model for an "infectious agent" has been proposed that is substantially different from our understanding of disease transmission by other microorganisms. Prion proteins have been implicated in many different diseases. Various transmission modes have been discovered, including consumption of infected meat, blood transfusion, medical devices used in neurosurgery and corneal transplantation, environmental routes (such as soil), and airborne routes. Familial and sporadic instances of the disease have also been recognized, such as fatal familial insomnia. Prion disease harbors long incubation periods, and subclinical infectious states have been discovered in asymptomatic individuals owing to lymphoreticular accumulation of PrPs. The uniformly fatal outcome after symptom onset secondary to prion disease has prompted rigorous research and attempts at development of prophylactic immunomodulatory techniques, gene therapy, and clinical trials investigating various medications such as doxycycline, quinacrine, pentosan polysulfate, and flupirtine to improve the survival and outcome in patients. In this article, we extensively review the background of PrPs and Creutzfeldt-Jakob disease, the various transmission methods, and recent developments into discovering a treatment for Creutzfeldt-Jakob disease. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Streptococcus pneumoniae Serotyping by a Single Polymerase Chain Reaction-Based Multiplex Assay.

Background: Streptococcus pneumoniae is a prominent pathogen in children younger than 5 years as well as elderly people. Capsular serotyping of S. pneumoniae is necessary to develop the new vaccines and prevent invasive and noninvasive infections by S. pneumoniae. In this study, we used 2-step multiplex polymerase chain reaction (mPCR) that contained primers to detect PCV13 (13-valent pneumococcal conjugated vaccine) and non-PCV13 serotypes in different clinical and normal flora samples. Methods: A total of 100 S. pneumoniae isolates were obtained between 2013 and 2015 in Tehran, Iran. The sources of isolates were clinical and normal flora. Clinical isolates were eye infection (26%), blood (19%), sputum (18%), sinusitis and cerebrospinal fluid (9% each), trachea (7%), pleural aspirate (3%), otitis (3%), and urine, bronchoalveolar lavage, and abscess (2% each). Moreover, 43 normal flora isolates were collected from healthy individuals. The strain isolates were tested for antimicrobial susceptibility and serotyped by mPCR. Results: The highest rate of resistance was seen for trimethoprim-sulfamethoxazole (96%) followed by tetracycline (77%), erythromycin (64%), clindamycin (56%), chloramphenicol (44%), and penicillin (26%). All isolates were susceptible to imipenem, ceftriaxone, vancomycin, linezolid, gemifloxacin, levofloxacin, moxifloxacin, and ofloxacin. By using mPCR, 91 and 7 isolates were typed in the first and second reactions, respectively. Two isolates were identified as nontypeable. The most frequent serotypes in 98 typeable serotypes were 23F (n = 21 [22%]), 14 (n = 19 [20%]), 3 (n = 13 [13%]), and 19F (n = 13 [13%]). Conclusions: Our multiplex assay is a precise and reliable method that can be used instead of the Quellung reaction for S. pneumoniae serotyping studies. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Access to healthcare for men and women with disabilities in the UK: secondary analysis of cross-sectional data

Objectives

The aim of this study was to investigate differences in access to healthcare between people with and without disabilities in the UK. The hypotheses were that: (1) people with disabilities would be more likely to have unmet healthcare needs and (2) there would be gender differences, with women more likely to report unmet needs.

Setting and participants

We performed secondary analysis, using logistic regressions, of deidentified cross-sectional data from the European Health Interview Survey, Wave 2. The sample included 12 840 community-dwelling people over the age of 16 from across the UK, 5 236 of whom had a disability. The survey method involved face-to-face and telephone interviews.

Outcome measures

Unmet need for healthcare due to long waiting lists or distance or transportation problems; not being able to afford medical examination, treatment, mental healthcare or prescribed medicines. All measures were self-reported.

Results

Adjusting for age, sex and other factors, people with a severe disability had higher odds of facing unmet needs. The largest gap was in 'unmet need for mental healthcare due to cost', where people with a severe disability were 4.5 times (CI 95% 2.2 to 9.2) more likely to face a problem, as well as in 'unmet need due to cost of prescribed medicine', where people with a mild disability had 3.6 (CI 95% 2.2 to 5.9) higher odds of facing a difficulty. Women with a disability were 7.2 times (CI 95% 2.7 to 19.4) more likely to have unmet needs due to cost of care or medication, compared with men with no disability.

Conclusions

People with disabilities reported worse access to healthcare, with transportation, cost and long waiting lists being the main barriers. These findings are worrying as they illustrate that a section of the population, who may have higher healthcare needs, faces increased barriers in accessing services.

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Values and preferences of women living with HIV who are pregnant, postpartum or considering pregnancy on choice of antiretroviral therapy during pregnancy

Objective

To investigate women's values and preferences regarding antiretroviral therapy (ART) during pregnancy to inform a BMJ Rapid Recommendation.

Setting

Primary studies reporting patient-reported outcomes relevant to decision-making regarding ART in any clinical and geographical setting.

Participants

Women living with HIV who are pregnant, postpartum or considering pregnancy.

Outcome measures

Quantitative measurements and qualitative descriptions of values and preferences in relation to ART during pregnancy. We also included studies on women's reported barriers and facilitators to adherence. We excluded studies correlating objective measures (eg, CD4 count) with adherence, or reporting only outcomes which are not expected to differ between ART alternatives (eg, access to services, knowledge about ART).

Results

We included 15 qualitative studies reporting values and preferences about ART in the peripartum period; no study directly studied choice of ART therapy during pregnancy. Six themes emerged: a desire to reduce vertical transmission (nine studies), desire for child to be healthy (five studies), concern about side effects to the child (eight studies), desire for oneself to be healthy (five studies), distress about side effect to oneself (10 studies) and pill burden (two studies). None of the studies weighed the relative importance of these outcomes directly, but pill burden/medication complexity appears to be a lower priority for most women compared with other factors. Overall, the body of evidence was at low risk of bias, with minor limitations.

Conclusions

Women who are or may become pregnant and who are considering ART appear to place a high value on both their own and their children's health. Evidence on the relative importance between these values when choosing between ART regimens is uncertain. There is variability in individual values and preferences among women. This highlights the importance of an individualised women-centred approach, such as shared decision-making when choosing between ART alternatives.

Trial registration number

International Prospective Register of Systematic Reviews:CRD42017057157.

http://ift.tt/2wlvu88

Antiretroviral therapy for pregnant women living with HIV or hepatitis B: a systematic review and meta-analysis

Objective

To assess the impact of various antiretroviral/antiviral regimens in pregnant women living with HIV or hepatitis B virus (HBV).

Design

We performed random effects meta-analysis for HIV-related outcomes and network meta-analysis for HBV outcomes, and used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework to assess quality separately for each outcome.

Data sources

Embase and Medline to February 2017.

Eligibility criteria

For maternal outcomes, we considered randomised controlled trials (RCTs) comparing tenofovir-based regimens with those with alternative nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). For child outcomes, we included RCTs and comparative observational studies of tenofovir-based regimens versus alternative NRTIs regimens or, for HBV, placebo.

Results

Ten studies (seven RCTs) met the inclusion criteria for maternal and child outcomes, and an additional 33 studies (12 RCTs) met the inclusion criteria for HBV-specific outcomes. The most common comparison was tenofovir and emtricitabine versus zidovudine and lamivudine. There was no apparent difference between tenofovir-based regimens and alternatives in maternal outcomes, including serious laboratory adverse events (low certainty) and serious clinical adverse events (moderate certainty). There was no difference between NRTIs in vertical transmission of HIV: 1 more per 1000, 8 fewer to 10 more, low certainty; or vertical transmission of HBV: 7 fewer per 1000, 10 fewer to 38 more, moderate certainty. We found moderate certainty evidence that tenofovir/emtricitabine increases the risk of stillbirths and early neonatal mortality (51 more per 1000, 11 more to 150 more) and the risk of early premature delivery at <34 weeks (42 more per 1000, 2 more to 127 more).

Conclusions

Tenofovir/emtricitabine is likely to increase stillbirth/early neonatal death and early premature delivery compared with zidovudine/lamivudine, but certainty is low when they are not coprescribed with lopinavir/ritonavir. Other outcomes are likely similar between antiretrovirals.

Trial registration number

PROSPERO CRD42017054392

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Efficacy and safety of controlled-release oxycodone/naloxone versus controlled-release oxycodone in Korean patients with cancer-related pain: a randomized controlled trial

Controlled-release oxycodone/naloxone (OXN-CR) maintains the effect of opioid-induced analgesia through oxycodone while reducing the occurrence rate of opioid-induced constipation through naloxone. The present...

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Antiinflammatory strategies in intrahepatic islet transplantation: a comparative study in preclinical models.

Background: The identification of pathway(s) playing a pivotal role in peritransplant detrimental inflammatory events represents the crucial step towards a better management and outcome of pancreatic islet transplanted patients. Recently, we candidate the CXCR1/2 inhibition as a relevant strategy in enhancing pancreatic islet survival after transplantation. Methods: Here, the most clinically used antiinflammatory compounds (IL1-receptor antagonist, steroids and TNF-[alpha] inhibitor) alone or in combination with a CXCR1/2 inhibitor were evaluated in their ability to improve engraftment or delay graft rejection. To rule out bias related to transplantation site, we used well-established preclinical syngeneic (250 C57BL/6 equivalent islets in C57BL/6) and allogeneic (400 Balb/c equivalent islets in C57BL6) intrahepatic islet transplantation platforms. Results: In mice, we confirmed that targeting the CXCR1/2 pathway is crucial in preserving islet function and improving engraftment. In the allogeneic setting, CXCR1/2 inhibitor alone could reduce the overall recruitment of transplant-induced leukocytes and significantly prolong the time to graft rejection both as single agent and in combination with immunosuppression. No other antiinflammatory compounds tested (IL1-receptor antagonist, steroids and TNF-[alpha] inhibitor) alone or in combination with CXCR1/2 inhibitor, improve islet engraftment and significantly delay graft rejection in the presence of MMF+FK-506 immunosuppressive treatment. Conclusions: These findings indicate that only the CXCR1/2-mediated axis plays a crucial role in controlling the islet damage and should be a target for intervention to improve the efficiency of islet transplantation. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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An unusual presentation of chronic cyanide toxicity from self-prescribed apricot kernel extract

Hypoxia under general anaesthesia is a potentially life-threatening condition. A seemingly well 67-year-old man appeared hypoxic with peripheral pulse oximetric measurement during routine anaesthesia. Postoperatively, the patient admitted to daily self-prescription of apricot kernel extract for a period of 5 years. Apricot kernel is a commonly taken extract used for a range of ailments, and is associated with cyanide toxicity, which was confirmed through blood analysis. Our explanation for the hypoxic measurement was the presence of free cyanide interfering with functioning of the peripheral pulse oximeter. On cessation of the apricot kernel extract, peripheral oxygen saturations returned to normal. Cardiac and respiratory causes together with rare haemoglobinopathies were excluded. This case illustrates how chronic dosing of complementary medicines can result in harmful toxicities, which may carry potential for serious consequences and how these chronic toxicities may present to physicians in atypical ways.

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Performance of a quick pregnancy test on whole blood in early pregnancy units: a prospective cohort study.

Objective: To assess the diagnostic performance of the NG-Test human chorionic gonadotropin (hCG) WB, which is a new point-of-care (POC) hCG whole-blood test. Materials and methods: This prospective study included women consulted in early pregnancy units for vaginal bleeding and/or pelvic pain with unknown pregnancy status after medical consultation including a pelvic ultrasound scan. A new POC test (the NG-Test hCG WB) and the usual laboratory serum test (considered the gold standard) were performed in patients. The results were interpreted in a blinded manner. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for the NG-Test hCG WB. Results: During the study period, 200 patients were included. The pregnancy rate was 17%. For the laboratory test, with a 5 UI/l hCG positivity threshold, the sensitivity, specificity, PPV, NPV, and Youden index of the NG-Test hCG WB were 89.7, 100, 100, 97.9, and 0.90%, respectively. Considering a 10 UI/l hCG positivity threshold, test sensitivity, specificity, PPV, NPV, and Youden index were 96.3, 100, 100, 99.3, and 0.96%, respectively. False-negative cases were either extremely brief pregnancies or residual hCG after miscarriage. The result was obtained within 5 min with the NG-Test hCG WB versus 90+/-31 min with the laboratory test. It was easy to use. Conclusion: The NG-Test hCG WB showed a high sensitivity, specificity, PPV, and NPV. Its use as triage in the case of a negative pelvic ultrasound exam is a potential strategy to improve patient flow, with an average time saving of 85 min. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Identifying palliative care needs in people with dementia.

Purpose of review: Dementia is now recognized as a progressive life-limiting illness where many patients can benefit from access to palliative care. Recent findings: The present review has focused on three areas namely, advanced care planning in supporting palliative care for dementia, hospice provision for people with dementia and provision of care within family home. In advanced care planning, there is little research on systematically developed and implemented advance care planning interventions or whether they achieve desired outcomes for end-of-life care. There is limited research on hospice-based care for patients with dementia and most studies are U.S. based. Equally studies exploring how family carers can be supported and facilitated to care at home for the person with dementia to the end of life are exploratory rather than determining what factors may be important. Summary: There are relatively few studies, especially quantitative studies or intervention studies being carried out to determine most effective means of providing palliative care for people with dementia, particularly with respect to advanced care planning, the provision of hospice-based care and support at home. Despite increased public awareness of dementia as a terminal illness, more research is required to support patients with dementia and their families at the end of life. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Emergency Reporting and First Due Size-Up announce integration and partnership to serve Fire and EMS department operations

Never again will a first responder be injured or worse due to a lack of information

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Duration of Sedentary Episodes Is Associated With Risk for Death

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Patterns of Sedentary Behavior and Mortality in U.S. Middle-Aged and Older Adults A National Cohort Study

Background:

Excessive sedentary time is ubiquitous in Western societies. Previous studies have relied on self-reporting to evaluate the total volume of sedentary time as a prognostic risk factor for mortality and have not examined whether the manner in which sedentary time is accrued (in short or long bouts) carries prognostic relevance.

Objective:

To examine the association between objectively measured sedentary behavior (its total volume and accrual in prolonged, uninterrupted bouts) and all-cause mortality.

Design:

Prospective cohort study.

Setting:

Contiguous United States.

Participants:

7985 black and white adults aged 45 years or older.

Measurements:

Sedentary time was measured using a hip-mounted accelerometer. Prolonged, uninterrupted sedentariness was expressed as mean sedentary bout length. Hazard ratios (HRs) were calculated comparing quartiles 2 through 4 to quartile 1 for each exposure (quartile cut points: 689.7, 746.5, and 799.4 min/d for total sedentary time; 7.7, 9.6, and 12.4 min/bout for sedentary bout duration) in models that included moderate to vigorous physical activity.

Results:

Over a median follow-up of 4.0 years, 340 participants died. In multivariable-adjusted models, greater total sedentary time (HR, 1.22 [95% CI, 0.74 to 2.02]; HR, 1.61 [CI, 0.99 to 2.63]; and HR, 2.63 [CI, 1.60 to 4.30]; P for trend < 0.001) and longer sedentary bout duration (HR, 1.03 [CI, 0.67 to 1.60]; HR, 1.22 [CI, 0.80 to 1.85]; and HR, 1.96 [CI, 1.31 to 2.93]; P for trend < 0.001) were both associated with a higher risk for all-cause mortality. Evaluation of their joint association showed that participants classified as high for both sedentary characteristics (high sedentary time [≥12.5 h/d] and high bout duration [≥10 min/bout]) had the greatest risk for death.

Limitation:

Participants may not be representative of the general U.S. population.

Conclusion:

Both the total volume of sedentary time and its accrual in prolonged, uninterrupted bouts are associated with all-cause mortality, suggestive that physical activity guidelines should target reducing and interrupting sedentary time to reduce risk for death.

Primary Funding Source:

National Institutes of Health.

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Treatment of Type 1 Diabetes: Synopsis of the 2017 American Diabetes Association Standards of Medical Care in Diabetes

Description:

The American Diabetes Association (ADA) annually updates Standards of Medical Care in Diabetes to provide clinicians, patients, researchers, payers, and other interested parties with evidence-based recommendations for the diagnosis and management of patients with diabetes.

Methods:

For the 2017 Standards of Care, the ADA Professional Practice Committee did MEDLINE searches from 1 January 2016 to November 2016 to add, clarify, or revise recommendations on the basis of new evidence. The committee rated the recommendations as A, B, or C, depending on the quality of evidence, or E for expert consensus or clinical experience. The Standards of Care were reviewed and approved by the Executive Committee of the ADA Board of Directors, which includes health care professionals, scientists, and laypersons. Feedback from the larger clinical community informed revisions.

Recommendation:

This synopsis focuses on recommendations from the 2017 Standards of Care about monitoring and pharmacologic approaches to glycemic management for type 1 diabetes.

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Tracking Our Physical Inactivity and Progression to Death: Is This Evolutionary Stagnation?

Diaz and colleagues' study tracked physical activity in adults aged 45 years or older and showed a strong relationship between daily volume of sedentary behavior and all-cause mortality, even after adjustment for episodes of moderate to vigorous physical activity. The editorialist discusses the findings and the strategies needed to reduce daily sedentary time and uninterrupted sedentary bout lengths.

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Distribution of Prescription Opioid Use Among Privately Insured Adults Without Cancer: United States, 2001–2013

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We Didn't Get Cold Feet

We didn't get cold feet—just very, very wet. That's what I e-mailed my wedding guests 5 days before our big day. My fiancé and I had been glued to our TV in Houston all weekend, watching Harvey make landfall and devastate our friends' and neighbors' lives.

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Diagnostic Reasoning: An Endangered Competency in Internal Medicine Training

Diagnostic reasoning is one of the most important skills of internal medicine physicians. However, given the complexities of the current health care environment, training in the diagnostic process has received less emphasis during internal medicine residency. In this essay, the authors describe several initiatives at their institution to foster the development of diagnostic reasoning skills among internal medicine residents.

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Romosozumab — Promising or Practice Changing?

Over the past decade, the osteoporosis landscape has changed. Even though more treatment options are available, fewer measurements of bone mass are being performed and fewer prescriptions for antiosteoporosis agents are being written — the last probably related to concerns about known side effects…

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Sophoridine induces apoptosis and S phase arrest via ROS-dependent JNK and ERK activation in human pancreatic cancer cells

Abstract

Background

Pancreatic cancer is generally acknowledged as the most common primary malignant tumor, and it is known to be resistant to conventional chemotherapy. Novel, selective antitumor agents are pressingly needed.

Methods

CCK-8 and colony formation assay were used to investigate the cell growth. Flow cytometry analysis was used to evaluate the cell cycle and cell apoptosis. The peroxide-sensitive fluorescent probe DCFH-DA was used to measure the intracellular ROS levels. Western blot assay was used to detect the levels of cell cycle and apoptosis related proteins. Xenografts in nude mice were used to evaluate the effect of Sophoridine on pancreatic cancer cell in vivo.

Results

Sophoridine killed cancer cells but had low cytotoxicity to normal cells. Pancreatic cancer cells were particularly sensitive. Sophoridine inhibited the proliferation of pancreatic cancer cells and induced cell cycle arrest at S phase and mitochondrial-related apoptosis. Moreover, Sophoridine induced a sustained activation of the phosphorylation of ERK and JNK. In addition, Sophoridine provoked the generation of reactive oxygen species (ROS) in pancreatic cancer cells. Finally, in vivo, Sophoridine suppressed tumor growth in mouse xenograft models.

Conclusion

These findings suggest Sophoridine is promising to be a novel, potent and selective antitumor drug candidate for pancreatic cancer.

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The induction of apoptosis and autophagy in human hepatoma SMMC-7721 cells by combined treatment with vitamin C and polysaccharides extracted from Grifola frondosa

Abstract

Polysaccharides extracted from the mushroom Grifola frondosa (GFP) are a potential anticancer agent. The objective of this study was to investigate the effect of GFP and vitamin C (VC) alone and in combination on the viability of human hepatocarcinoma SMMC-7721 and HepG2 cells. Studies designed to detect cell apoptosis and autophagy were also conducted to investigate the mechanism. Results from the cell viability assay indicated that a combination of GFP (0.2 or 0.25 mg/mL) and VC (0.3 mmol/L) (GFP/VC) led to 52.73 and 53.93% reduction in cell viability of SMMC-7721 and HepG2 cells separately after 24 h. Flow cytometric analysis indicated that GFP/VC treatment induced cell cycle arrest at the G2/M phase, and apoptosis occurred in approximately 43.62 and 42.46% of the SMMC-7721 and HepG2 cells separately. Moreover, results of Hoechst33258 and monodansylcadaverine staining, and transmission electron microscopy, showed that GFP/VC induced apoptosis and autophagy in SMMC-7721 and HepG2 cells. Western blot analysis showed changes in the expression of apoptosis-related proteins [upregulation of BAX and caspase-3, downregulation of Bcl-2, and activation of poly-(ADP-ribose)-polymerase] and autophagy protein markers (upregulation of beclin-1 and microtubule-associated protein 1A/1B light chain-3). We also demonstrated that the expression of both Akt and p-Akt was enhanced, suggesting the PI3K/Akt/mTOR pathway might not be involved in this process. Our study shows that the combined application of GFP and VC induced cell apoptosis and autophagy in vitro, and might have antitumor activity in vivo.

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XIAP over-expression is an independent poor prognostic marker in Middle Eastern breast cancer and can be targeted to induce efficient apoptosis

Abstract

Background

Breast cancer is the most common cancer in females and is ranked second in cancer-related deaths all over the world in women. Despite improvement in diagnosis, the survival rate of this disease has still not improved. X-linked Inhibitor of Apoptosis (XIAP) has been shown to be over-expressed in various cancers leading to poor overall survival. However, the role of XIAP in breast cancer from Middle Eastern region has not been fully explored.

Methods

We examined the expression of XIAP in more than 1000 Middle Eastern breast cancer cases by immunohistochemistry. Apoptosis was measured by flow cytometry. Protein expression was determined by western blotting. Finally, in vivo studies were performed on nude mice following xenografting and treatment with inhibitors.

Results

XIAP was found to be over-expressed in 29.5% of cases and directly associated with clinical parameters such as tumor size, extra nodal extension, triple negative breast cancer and poorly differentiated breast cancer subtype. In addition, XIAP over-expression was also significantly associated with PI3-kinase pathway protein; p-AKT, proliferative marker; Ki-67 and anti-apoptotic marker; PARP. XIAP over-expression in our cohort of breast cancer was an independent poor prognostic marker in multivariate analysis. Next, we investigated inhibition of XIAP using a specific inhibitor; embelin and found that embelin treatment led to inhibition of cell viability and induction of apoptosis in breast cancer cells. Finally, breast cancer cells treated with combination of embelin and PI3-kinase inhibitor; LY294002 synergistically induced apoptosis and caused tumor growth regression in vivo.

Conclusion

These data suggest that XIAP may be playing an important role in the pathogenesis of breast cancer and can be therapeutically targeted either alone or in combination with PI3-kinase inhibition to induce efficient apoptosis in breast cancer cells.

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Characterization of Skull Base Lesions Using Pseudo-Continuous Arterial Spin Labeling

Abstract

Purpose

Pseudo-continuous arterial spin labeling (pCASL) is a non-invasive magnetic resonance (MR) perfusion technique. Our study aimed at estimating the diagnostic performance of the pCASL sequence in assessing the perfusion of skull base lesions both qualitatively and quantitatively and at providing cut-off values for differentiation of specific skull base lesions.

Methods

In this study 99 patients with histopathologically confirmed skull base lesions were retrospectively enrolled. Based on a pathological analysis, the lesions were classified as hypervascular and non-hypervascular. Patients were divided into two subgroups according to the anatomical origin of each lesion. The MRI study included pCASL and 3D T1-weighted fat-saturated post-contrast sequences. Of the patients seven were excluded due to technical difficulties or patient movement. The lesions were classified by two raters, blinded to the diagnosis as either hyperperfused or non-hyperperfused, based on the pCASL sequence. The normalized tumor blood flow (nTBF) of each lesion was determined. Qualitative and quantitative characteristics of hypervascular and non-hypervascular lesions were compared.

Results

Visual assessment enabled correct classification of 98% of the lesions to be performed. Quantitatively, we found significant differences between the nTBF values for hypervascular and non-hypervascular lesions (p < 0.001) and provided cut-off values, allowing meningioma and schwannoma to be distinguished from meningioma and adenoma. Significant differences were also found within the hypervascular group, namely, paraganglioma was more hyperperfused than meningioma (p = 0.003) or metastases (p = 0.009).

Conclusion

The present study demonstrates the high diagnostic performance of pCASL in characterizing skull base lesions by either visual assessment or nTBF quantification. Adding the pCASL sequence to the conventional protocol of skull base assessment can be recommended.

http://ift.tt/2eRzbMw

LanguageMAPS adds to its medical advisory board

DALLAS — LanguageMAPS, creator of the 1st Minute App and leader in simplified language translation for emergencies, is pleased to announce the addition of Dr. Patti C. Huang and Dr. Tyler DeLange as new members of its medical advisory board. Dr. Patti Huang Dr. Huang runs Frisco Family ENT in North Texas and has won "Best Doctor" awards from D Magazine since 2012. She is also the creator ...

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Long-lasting complete response status of advanced stage IV gall bladder cancer and colon cancer after combined treatment including autologous formalin-fixed tumor vaccine: two case reports

Abstract

Background

The prognosis of advanced (stage IV) cancer of the digestive organs is very poor. We have previously reported a case of advanced breast cancer with bone metastasis that was successfully treated with combined treatments including autologous formalin-fixed tumor vaccine (AFTV). Herein, we report the success of this approach in advanced stage IV (heavily metastasized) cases of gall bladder cancer and colon cancer.

Case presentation

Case 1: A 61-year-old woman with stage IV gall bladder cancer (liver metastasis and lymph node metastasis) underwent surgery in May 2011, including partial resection of the liver. She was treated with AFTV as the first-line adjuvant therapy, followed by conventional chemotherapy. This patient is still alive without any recurrence, as confirmed with computed tomography, for more than 5 years.

Case 2: A 64-year-old man with stage IV colon cancer (multiple para-aortic lymph node metastases and direct abdominal wall invasion) underwent non-curative surgery in May 2006. Following conventional chemotherapy, two courses of AFTV and radiation therapy were administered sequentially. This patient has had no recurrence for more than 5 years.

Conclusion

We report the success of combination therapy including AFTV in cases of liver-metastasized gall bladder cancer and abdominal wall-metastasized colon cancer. Both patients experienced long-lasting, complete remission. Therefore, combination therapies including AFTV should be considered in patients with advanced cancer of the digestive organs.

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Cell-specific mechanisms of TMEM16A Ca 2+ -activated chloride channel in cancer

Abstract

TMEM16A (known as anoctamin 1) Ca²⁺-activated chloride channel is overexpressed in many tumors. TMEM16A overexpression can be caused by gene amplification in many tumors harboring 11q13 amplification. TMEM16A expression is also controlled in many cancer cells via transcriptional regulation, epigenetic regulation and microRNAs. In addition, TMEM16A activates different signaling pathways in different cancers, e.g. the EGFR and CAMKII signaling in breast cancer, the p38 and ERK1/2 signaling in hepatoma, the Ras-Raf-MEK-ERK1/2 signaling in head and neck squamous cell carcinoma and bladder cancer, and the NFκB signaling in glioma. Furthermore, TMEM16A overexpression has been reported to promote, inhibit, or produce no effects on cell proliferation and migration in different cancer cells. Since TMEM16A exerts different roles in different cancer cells via activation of distinct signaling pathways, we try to develop the idea that TMEM16A regulates cancer cell proliferation and migration in a cell-dependent mechanism. The cell-specific role of TMEM16A may depend on the cellular environment that is predetermined by TMEM16A overexpression mechanisms specific for a particular cancer type. TMEM16A may exert its cell-specific role via its associated protein networks, phosphorylation by different kinases, and involvement of different signaling pathways. In addition, we discuss the role of TMEM16A channel activity in cancer, and its clinical use as a prognostic and predictive marker in different cancers. This review highlights the cell-type specific mechanisms of TMEM16A in cancer, and envisions the promising use of TMEM16A inhibitors as a potential treatment for TMEM16A-overexpressing cancers.

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Stereotactic Atlas-Guided Laser Capture Microdissection of Brain Regions Affected by Traumatic Injury

We describe the use of laser capture microdissection to obtain samples of distinct cell populations from different brain regions for gene and microRNA analysis. This technique allows the study of differential effects of traumatic brain injury in specific regions of the rat brain.

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Tumor infiltrating lymphocytes in lymph node metastases of stage III melanoma correspond to response and survival in nine patients treated with ipilimumab at the time of stage IV disease

Abstract

Prognosis of metastatic melanoma improved with the development of checkpoint inhibitors. The role of tumor infiltrating lymphocytes (TILs) in lymph node metastases of stage III melanoma remains unclear. We retrospectively characterized TILs in primary melanomas and matched lymph node metastases (stage III melanoma) of patients treated with the checkpoint inhibitor ipilimumab. Tumor infiltrating lymphocytes were characterized for CD3, CD4, and CD8 expressions by immunohistochemistry. 4/9 patients (44%) responded to treatment with ipilimumab (1 complete and 2 partial remissions, 1 stable disease). All responders exhibited CD4 and CD8 T-cell infiltration in their lymph node metastases, whereas all non-responders did not show an infiltration of the lymph node metastasis with TILs. The correlation between the presence and absence of TILs in responders vs. non-responders was statistically significant (p = 0.008). Median distant metastases free survival, i.e., progression from stage III to stage IV melanoma, was similar in responders and non-responders (22.1 vs. 19.3 months; p = 0.462). Median progression free and overall survival show a trend in favor of the patients having TIL rich lymph node metastases (6.8 vs. 3.3 months, p = 0.09; and all alive at last follow-up vs. 8.2 months, respectively, p = 0.08). Our data suggest a correlation between the T-cell infiltration of the lymph node metastases in stage III melanoma and the response to ipilimumab once these patients progress to stage IV disease.

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CAR T-Cell Therapy Approved for Some Children and Young Adults with Leukemia

FDA has approved tisagenlecleucel (Kymriah™), a type of immunotherapy called CAR T-cell therapy, for some children and young adults with advanced acute lymphoblastic leukemia (ALL).

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Tumor infiltrating lymphocytes in lymph node metastases of stage III melanoma correspond to response and survival in nine patients treated with ipilimumab at the time of stage IV disease

Abstract

Prognosis of metastatic melanoma improved with the development of checkpoint inhibitors. The role of tumor infiltrating lymphocytes (TILs) in lymph node metastases of stage III melanoma remains unclear. We retrospectively characterized TILs in primary melanomas and matched lymph node metastases (stage III melanoma) of patients treated with the checkpoint inhibitor ipilimumab. Tumor infiltrating lymphocytes were characterized for CD3, CD4, and CD8 expressions by immunohistochemistry. 4/9 patients (44%) responded to treatment with ipilimumab (1 complete and 2 partial remissions, 1 stable disease). All responders exhibited CD4 and CD8 T-cell infiltration in their lymph node metastases, whereas all non-responders did not show an infiltration of the lymph node metastasis with TILs. The correlation between the presence and absence of TILs in responders vs. non-responders was statistically significant (p = 0.008). Median distant metastases free survival, i.e., progression from stage III to stage IV melanoma, was similar in responders and non-responders (22.1 vs. 19.3 months; p = 0.462). Median progression free and overall survival show a trend in favor of the patients having TIL rich lymph node metastases (6.8 vs. 3.3 months, p = 0.09; and all alive at last follow-up vs. 8.2 months, respectively, p = 0.08). Our data suggest a correlation between the T-cell infiltration of the lymph node metastases in stage III melanoma and the response to ipilimumab once these patients progress to stage IV disease.

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Distinct molecular subtypes of uterine leiomyosarcoma respond differently to chemotherapy treatment

Abstract

Background

Uterine leiomyosarcoma (ULMS) is an aggressive form of soft tissue tumors. The molecular heterogeneity and pathogenesis of ULMS are not well understood.

Methods

Expression profiling data were used to determine the possibility and optimal number of ULMS molecular subtypes. Next, clinicopathological characters and molecular pathways were analyzed in each subtype to prospect the clinical applications and progression mechanisms of ULMS.

Results

Two distinct molecular subtypes of ULMS were defined based on different gene expression signatures. Subtype I ULMS recapitulated low-grade ULMS, the gene expression pattern of which resembled normal smooth muscle cells, characterized by overexpression of smooth muscle function genes such as LMOD1, SLMAP, MYLK, MYH11. In contrast, subtype II ULMS recapitulated high-grade ULMS with higher tumor weight and invasion rate, and was characterized by overexpression of genes involved in the pathway of epithelial to mesenchymal transition and tumorigenesis, such as CDK6, MAPK13 and HOXA1.

Conclusions

We identified two distinct molecular subtypes of ULMS responding differently to chemotherapy treatment. Our findings provide a better understanding of ULMS intrinsic molecular subtypes, and will potentially facilitate the development of subtype-specific diagnosis biomarkers and therapy strategies for these tumors.

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BRCA2 carriers with male breast cancer show elevated tumour methylation

Abstract

Background

Male breast cancer (MBC) represents a poorly characterised group of tumours, the management of which is largely based on practices established for female breast cancer. However, recent studies demonstrate biological and molecular differences likely to impact on tumour behaviour and therefore patient outcome. The aim of this study was to investigate methylation of a panel of commonly methylated breast cancer genes in familial MBCs.

Methods

60 tumours from 3 BRCA1 and 25 BRCA2 male mutation carriers and 32 males from BRCAX families were assessed for promoter methylation by methylation-sensitive high resolution melting in a panel of 10 genes (RASSF1A, TWIST1, APC, WIF1, MAL, RARβ, CDH1, RUNX3, FOXC1 and GSTP1). An average methylation index (AMI) was calculated for each case comprising the average of the methylation of the 10 genes tested as an indicator of overall tumour promoter region methylation. Promoter hypermethylation and AMI were correlated with BRCA carrier mutation status and clinicopathological parameters including tumour stage, grade, histological subtype and disease specific survival.

Results

Tumours arising in BRCA2 mutation carriers showed significantly higher methylation of candidate genes, than those arising in non-BRCA2 familial MBCs (average AMI 23.6 vs 16.6, p = 0.01, 45% of genes hypermethylated vs 34%, p < 0.01). RARβ methylation and AMI-high status were significantly associated with tumour size (p = 0.01 and p = 0.02 respectively), RUNX3 methylation with invasive carcinoma of no special type (94% vs 69%, p = 0.046) and RASSF1A methylation with coexistence of high grade ductal carcinoma in situ (33% vs 6%, p = 0.02). Cluster analysis showed MBCs arising in BRCA2 mutation carriers were characterised by RASSF1A, WIF1, RARβ and GTSP1 methylation (p = 0.02) whereas methylation in BRCAX tumours showed no clear clustering to particular genes. TWIST1 methylation (p = 0.001) and AMI (p = 0.01) were prognostic for disease specific survival.

Conclusions

Increased methylation defines a subset of familial MBC and with AMI may be a useful prognostic marker. Methylation might be predictive of response to novel therapeutics that are currently under investigation in other cancer types.

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Concordance of Adherence Measurement Using Self-Reported Adherence Questionnaires and Medication Monitoring Devices: An Updated Review

Abstract

Introduction

As medication adherence continues to be a prevalent issue in today's society, the methods used to monitor medication-taking behaviors are constantly being re-evaluated and compared in search of the 'gold standard' measure. Our review aimed to assess the current literature surrounding the correlation between self-reported questionnaires (SRQs) and electronic monitoring devices to determine if these measures produce similar results.

Methods

We performed a literature search from 2009 to 2017 using PubMed, PubMed In-Process and Non-Indexed, EMBASE, Ovid MEDLINE, and Ovid MEDLINE In-Process. A keyword search using the terms 'patient compliance', 'treatment compliance', 'medication adherence', 'drug monitoring', 'drug therapy', 'electronic', 'digital', 'computer', 'monitor', 'monitoring', 'drug', 'pharmaceutical preparations', 'compliance', and 'medications' was done to capture all articles. We included articles measuring adherence using both monitoring devices and SRQs.

Results

Thirty-five articles were included in this review. The average difference in measured adherence rates between the two measures was 9.2% (range −66.3 to 61.5). A majority (62.7%) of articles reported moderate (n = 12; 27.9%), high (n = 5, 11.6%), or significant (n = 10, 23.3%) correlations between SRQs and monitoring devices.

Conclusion

Results from our review are consistent with previous studies, as we found that many of our studies produced moderate to high correlation between both SRQs and monitoring devices [Farmer, Clin Ther 21(6):1074–90 (1999), IMS Institute for Healthcare Informatics. Avoidable costs in US health care (2012), Patel et al., Respirology 18(3):546–52 (2013), Siracusa et al., J Cyst Fibros 14(5):621–6 (2015), Smith et al., Int J Cardiol 145(1):122–3 (2010)]. Our findings demonstrate that self-reported adherence produces comparable results to electronic monitoring devices. As there is not yet a 'gold standard' measure for monitoring patient adherence, SRQs and Medication Event Monitoring Systems (MEMS) operating together continue to emerge as the preferred effective method for measuring medication adherence.

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Responsible pricing in value-based assessment of cancer drugs: real-world data are an inevitable addition to select meaningful new cancer treatments

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DNAJC12 and dopa-responsive non-progressive Parkinsonism

ABSTRACT

Biallelic DNAJC12 mutations were described in children with hyperphenylalaninemia, neurodevelopmental delay, and dystonia.

We identified DNAJC12 homozygous null variants (c.187A>T;p.K63*and c.79-2A>G;p.V27Wfs*14) in two kindreds with early-onset parkinsonism. Both probands had mild intellectual disability, mild non-progressive, motor symptoms, sustained benefit from small dose of levodopa and substantial worsening of symptoms after levodopa discontinuation. Neuropathology (Proband-A) revealed no alpha-synuclein pathology and substantia nigra depigmentation with moderate cell loss DNAJC12 transcripts were reduced in both patients. Our results suggest DNAJC12 mutations (absent in 500 early-onset patients with Parkinson's disease) rarely cause dopa-responsive non-progressive parkinsonism in adulthood, broadening the clinical spectrum of DNAJC12 deficiency. This article is protected by copyright. All rights reserved.

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Bicycling suppresses abnormal beta synchrony in the Parkinsonian basal ganglia

Abstract

Objective:

Freezing of gait is a poorly understood symptom of Parkinson's disease, and can severely disrupt the locomotion of affected patients. However, bicycling ability remains surprisingly unaffected in most patients suffering from freezing suggesting functional differences in the motor network. The purpose of this study was to characterize and contrast the oscillatory dynamics underlying bicycling and walking in the basal ganglia.

Methods:

We present the first local field potential recordings directly comparing bicycling and walking in Parkinson's disease patients with electrodes implanted in the subthalamic nuclei for deep brain stimulation. Low (13-22 Hz) and high (23-35 Hz) beta power changes were analyzed in 22 subthalamic nuclei from 13 Parkinson's disease patients (57.5 +/- 5.9 years, four female). The study group consisted of five patients with and eight patients without freezing of gait.

Results:

In patients without freezing of gait, both bicycling and walking led to a suppression of subthalamic beta power (13-35 Hz), and this suppression was stronger for bicycling. Freezers showed a similar pattern in general. Superimposed on this pattern, however, we observed a movement-induced, narrowband power increase around 18 Hz, which was evident even in the absence of freezing.

Interpretation:

These results indicate that bicycling facilitates overall suppression of beta power. Furthermore, movement leads to exaggerated synchronization in the low beta band specifically within the basal ganglia of patients susceptible to freezing. Abnormal ∼18 Hz oscillations are implicated in the pathophysiology of freezing of gait, and suppressing them may form a key strategy in developing potential therapies. This article is protected by copyright. All rights reserved.

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Brain-heart interactions reveal consciousness in non-communicating patients

Abstract

Objective

We here aimed at characterizing heart-brain interactions in patients with disorders of consciousness. We tested how this information impacts data-driven classification between unresponsive and minimally conscious patients.

Methods

A cohort of 127 patients in vegetative state/unresponsive wakefulness syndrome (VS/UWS, n=70) and minimally conscious state (MCS, n=57) were presented with the 'Local-Global' auditory oddball paradigm, which distinguishes two levels of processing: short-term deviation of local auditory regularities and global long-term rule violations. In addition to previously validated markers of consciousness extracted from electroencephalograms (EEG), we computed autonomic cardiac markers, such as heart rate and variability (HR, HRV), and cardiac cycle phase-shifts triggered by the processing of the auditory stimuli.

Results

HR and HRV were similar in patients across groups. The cardiac cycle was not sensitive to the processing of local regularities in either the VS/UWS or MCS patients. In contrast, global regularities induced a phase-shift of the cardiac cycle exclusively in the MCS group. The interval between the auditory stimulation and the following R-peak was significantly shortened in MCS when the auditory rule was violated. When the information of the cardiac cycle modulations and other consciousness-related EEG markers were combined, single-patient classification performance was enhanced compared to classification with solely EEG markers.

Interpretation

Our work shows a link between residual cognitive processing and the modulation of autonomic somatic markers. These results open a new window to evaluate patients with disorders of consciousness via the embodied paradigm, according to which body-brain functions contribute to a holistic approach to conscious processing. This article is protected by copyright. All rights reserved.

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Mutations of KIF14 Cause Primary Microcephaly by Impairing Cytokinesis

ABSTRACT

Objective: Autosomal recessive primary microcephaly (MCPH) is a rare condition characterized by a reduced cerebral cortex accompanied with intellectual disability. Mutations in 17 genes have been shown to cause this phenotype. Recently, mutations in CIT, encoding CRIK (Citron Rho-interacting kinase) — a component of the central spindle matrix, were added. We aimed at identifying novel MCPH-associated genes and exploring their functional role in pathogenesis.

Methods: Linkage analysis and whole-exome sequencing were performed in consanguineous and nonconsanguineous MCPH families to identify disease-causing variants. Functional consequences were investigated by RNA studies and on cellular level using immunofluorescence and microscopy.

Results: We identified homozygous mutations in KIF14 (NM_014875.2;c.263T>A;pLeu88*, c.2480_2482delTTG;p.Val827del and c.4071G>A;p.Gln1357=) as the likely cause in three MCPH families. Further, in a patient presenting with a severe form of primary microcephaly and short stature, we identified compound heterozygous missense mutations in KIF14 (NM_014875.2;c.2545C>G;p.His849Asp and c.3662G>T;p.Gly1221Val). Three of the five identified mutations impaired splicing and two resulted in a truncated protein. Intriguingly, Kif14 knockout mice also showed primary microcephaly. Human kinesin-like protein KIF14, a microtubule motor protein, localizes at the midbody to finalize cytokinesis by interacting with CRIK. We found impaired localization of both KIF14 and CRIK at the midbody in patient-derived fibroblasts. Further, we observed a large number of binucleated and apoptotic cells — signs of failed cytokinesis that we also observed in experimentally KIF14-depleted cells.

Interpretation: Our data corroborate the role of an impaired cytokinesis for the etiology of primary and syndromic microcephaly as has been proposed by recent findings on CIT mutations. This article is protected by copyright. All rights reserved.

http://ift.tt/2gWRNPm